R(-) deprenyl (also known as L-deprenyl), N,.alpha.-dimethyl-N-2propenylphenethylamine) is a well-known inhibitor of the B-form of monoamine oxidase enzyme (hereinafter "MAO-B").
PCT International Application No. WO92/17169 describes the activity of R(-) deprenyl in maintaining, preventing the loss of, or recovering nerve growth function. This publication includes a list of deprenyl-like derivatives that are suggested to possess similar activities, althought no data is given in support of this contention. Included in the list is AGN-1135 which is racemic N=propargyl-1-aminoindan.
In a subsequent article Tatton, W. G. et al., J. Neuroscience, 13(9), pp. 4042-4053, (1993) report that the neuroprotective activity of deprenyl is limited to the R(-) enantiomer. The S(-) enantiomer was 2000 times less active in increasing the survival of axotomized immature rat facial mononeurons. Furthermore, it was demonstrated that neuroprotective activity is associated only with the R-enantiomers of propargyl derivatives that posses MAO-B inhibitory activity. Davis et al., J. Neurochem. Supplement 1, 64:S60, (1995) (recording the data presented by the same author at the Twenty-sixth Meeting of the American Society for Neuro-chemistry, held in Santa Monica, Calif., USA on Mar. 5-9, 1995) disclosed that in various models of neuroprotective activity, the R--' enantiomers of certain aliphatic N-methylpropargylamines that are selective inhibitors of MAO-B, were more effective in rescuing damaged neurons than their corresponding S-enantiomers.
The development of the work on deprenyl has led to the belief that the neuroprotective activity does not involve inhibition of MAO-B, because sub-inhibitory levels of R(-) deprenyl have been observed to prevent nerve cell death (Tatton, Movement Disorders, 8(1):S20-S30, (1993)). It has been proposed that R(-) deprenyl is perhaps dependent on interaction with a subtype of MAO-B that possesses extreme sensitivity to R(-) deprenyl.
Yu et al., J. Neurosci, 63, pp. 1820-1827, (1994) have assessed the activity of R(-)- and S(+)-deprenyl and several aliphatic propargylamine derivatives in reversing the noradrenaline depletion in rodents induced by the administration of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4). The end-point measured and described as an indication of "neuroprotective activity" was the percent restoration of noradrenaline as compared to untreated controls. In the results described, R(-) deprenyl and several of the higher N-aliphatically substituted propargylamines displayed "neuroprotective activity". S(+) deprenyl was described as acting like the known noradrenaline uptake inhibitor desipramine, having a far lower "neuroprotective activity" in comparison with R(-) deprenyl. In summary, S(+) deprenyl was shown to be a superior noradrenaline uptake inhibitor as compared to R(-) deprenyl, yet far inferior in the described measure of "neuro-protective activity".
European Patent 436,492 discloses that R(+) enantiomer of N-propargyl-1-aminoindan (hereinafter referred to as "R(+)PAL") as a selective irreversible inhibitor of MAO-B. Due to this specific activity R(+)PAI has also been proposed for use in the treatment of Parkinson's Disease, memory disorders, dementia (particularly of the Alzheimer's type) depression and hyperactive syndrome in children. U.S. Pat. Nos. 5,387,612, 5,453,446 and 5,457,133 relate to R(+)PAI and to methods of treating patients suffering from Parkinson's Disease comprising administering R(+)PAI to the patient. In these U.S. patents emphasis is placed on the superior MAO-B inhibitory activity of R(+)PAI as compared to its antipode, the S(-) enantiomer of N-propargyl-1-aminoindan (hereinafter referred to as "S(-)PAI"). In in vitro assays R(+)PAI was found to be nearly 7,000 times more active as an inhibitor of MAO-B than S(-)PAI. It was also found in these assays that, whereas R(+)PAI is more than 29 times more selective for MAO-B than MAO-A (the A-form of monoamine oxidase enzyme), S(-)PAI showed no preference to either substrate. This effect was also observed in both acute a chronic in vivo administration.
PCT International Application Publication No. WO95/11016 further disclosed that R(+)PAI is active as a "neuroprotective agent". The data therein describes its use in the prevention of NMDA induced cell death in rat cerebellum cells as well as in slowing neuronal degeneration when administered after crushing the rat optic nerve. No indication is given in this publication as regards the mechanism by which R(+)PAI may exert its "neuroprotective" effect.
The use of MAO inhibitors as neuronal rescue agents in clinical situations where neuronal survival is in jeopardy, might involve the important disadvantage resulting from their potential cardiovascular side-effects, alone or following drug-drug or drug-food interactions. These side-effects are attributed to partial or total inhibition of peripheral MAO-A, resulting in excessive concentrations of norepinephrine in the cardiovascular system (see for example, Physicians' Desk Reference 48th Edition, 1994, Medical Economics Data, Montvale, N.J., under Eldepryl). Selective MAO-B inhibitors such as R(-) deprenyl are less prone to compromise the cardiovascular system than the less specific agents such as pargyline or clorgyline, hence the former are probably the safer agents. However, the MAO subtype selectivity of these agents as determined under in vitro conditions tends to decrease dramatically when determined in vivo. Thus, the ratio to the in vitro IC.sub.50 values of MAO-A/MAO-B for R(-) deprenyl has been reported by various authors as 400, 247, 360 and 16 (from a compilation by W. Paul and I. Szelenyi, in "Inhibitors of Monoamine Oxidase-B", I Szelnyi editor, Birkhauser, Basel, p. 353, 1993), suggesting a safety factor of about 100 or more. The recommended daily dose of R(-) deprenyl in human subjects is 10 mg, with 30-40 mg considered as the dose at which cardiovascular function could be compromised (Physicians' Desk Reference supra). Thus, the safety factor in clinical practice is about 3 to 4, as compared to about 400 in experimental systems in vitro.
There still exists, therefore, a need for a "neuroprotective agent" that, while being effective is free from the side-effects associated with hitherto known neuroprotectants of the MAO-B inhibitor type.